DESCRIPTION, OVERALL (provided by applicant): The University of Michigan is ideally poised to house a MAPP Discovery Site. The faculty of the Chronic Pain and Fatigue Research Center (CPFRC) are internationally known for translational research in fibromyalgia (FM) and related illnesses, including interstitial cystitis/painful bladder syndrome (IC/PBS). The Center has begun collaborating with a strong group of colleagues from the DM Urology Department. These investigators have expertise that spans the translational bench to community continuum of IC and chronic pelvic pain. All of our projects will pursue a unifying hypothesis that we feel has been supported in related pain conditions and may underlie IC/PBS: A subset of women with IC/PBS has a central problem in pain or sensory processing, as occurs in FM, rather than a disorder confined to the bladder. Project one extends the ongoing NIH-funded RICE study (a cross-sectional epidemiological study that queries individuals in the U.S. regarding their current symptoms). This study will 1) examine the natural history of IC/PBS in the general population, 2) show that IC/PBS patients in tertiary care clinical samples have higher rates of co-morbid conditions, including psychological co-morbidities, than IC/PBS patients in the population, and will also identify a population-based cohort of IC/PBS patients in the Michigan region that can be recruited for studies at our discovery site. Project two will perform experimental sensory testing and functional neuroimaging in women with IC/PBS, healthy controls, and FM patients. We hypothesize that IC/PBS patients are diffusely sensitive to pain and other sensory stimuli, similar to FM patients. Project three will further explore the precise reason(s) for the augmented pain and sensory processing seen in IC/PBS. A specific molecular probe will test whether a subset of IC/PBS patients has attenuated descending analgesic activity that is restored via administration of a selective noradrenergic/serotonergic reuptake inhibitor (NSRI), milnacipran. We hypothesize that we will show via experimental pain testing and functional neuroimaging that there is attenuated descending analgesic activity in some IC/PBS patients, and that improvements in these experimental parameters will be accompanied by improvement in pain and urinary urgency/frequency. We also hypothesize that certain genetic polymorphisms in COMT and beta-2 and-3 adrenoreceptors will predict the magnitude of the descending analgesic response, and response to a NSRI.